NCI CANCERLIT^® Search: Plasma Cell Neoplasm - September 2001

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Ultima Vez Modificado: 1 de noviembre del 2001

Apoptosis in multiple myeloma: therapeutic implications.
Analysis of clonal relationship using single-cell polymerase chain reaction in a patient with concomitant mantle cell lymphoma and multiple myeloma.
[Laryngeal plasmacytoma]
Serum cystatin C in patients with myeloma.
[A patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma]
Expression of granzyme B and perforin in multiple myeloma.
The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.
[Activation of autologous hematopoietic stem cell transplants with interleukin-2]
Expression of nitric oxide synthase isoforms and nitrotyrosine immunoreactivity by B-cell non-Hodgkin's lymphomas and multiple myeloma.
Thalidomide in the treatment of plasma cell malignancies.
Glomerular filtration rate prior to high-dose melphalan 200 mg/m(2) as a surrogate marker of outcome in patients with myeloma.
Accumulation of Tc-99m HMDP in extramedullary plasmacytoma of the stomach.
Thalidomide use: past history and current implications for practice.
Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma.
Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.
Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells.
Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk.
Technetium-99m-sestamibi scintigraphy: an alternative approach for diagnosis and follow-up of active myeloma lesions after high-dose chemotherapy and autologous stem cell transplantation.
High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions.
Predictive value of technetium-99m sestamibi in patients with multiple myeloma and potential role in the follow-up.
Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma.
Metastatic transitional cell carcinoma or nonsecretory multiple myeloma?
Multiple myeloma presenting as a painful mandibular swelling: a case report.
[40 years ago in Medicina Clinica. The introduction of melphalan in Spain]
[Intracytoplasmic crystals and Fanconi syndrome in a patient with IgA kappa myeloma]
Protein kinase C delta and eta isoenzymes control the shedding of the interleukin 6 receptor alpha in myeloma cells.
The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance.
T-cell--depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect.
Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosis in myeloma cell lines.
alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells.
Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3.
Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging.
Deregulated cytokine network and defective Th1 immune response in multiple myeloma.
Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
A case of meningeal myeloma presenting as obstructive hydrocephalus--a therapeutic challenge.
OPP-EBV-CAD regimen as salvage treatment in advanced refractory or resistant multiple myeloma.
Primary testicular plasmacytoma with hydrocele of the testis.
Expression of a free gamma heavy chain in serum following autologous stem cell transplantation for IgG kappa multiple myeloma.
Immunoglobulin D myeloma presenting as an extraosseous soft tissue tumor.
Plasmacytoma of the larynx diagnosed by fine-needle aspiration cytology: a case report.
Plasmacytoma of the superficial radial nerve.
Extramedullary plasmacytoma of the hand: a case report.
[Skin location of multiple myeloma mimicking a vascular tumor]
Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14).
Evidence of a role for a non-matrix-type metalloproteinase activity in the shedding of syndecan-1 from human myeloma cells.
Expression of IL-6 and IL-6 receptors by circulating clonotypic B cells in multiple myeloma: potential for autocrine and paracrine networks.
Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

CancerMail from the National Cancer Institute

1
UI - 21217323
AU - Chauhan D; Anderson KC
TI - Apoptosis in multiple myeloma: therapeutic implications.
SO - Apoptosis 2001 Feb-Apr;6(1-2):47-55
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Apoptosis is the primary means by which most radio- and chemotherapy modalities kill cancer cells, and abnormalities in the apoptotic pathways may contribute to disease pathogenesis of cancer. Multiple Myeloma (MM) is a hematological malignancy which will affect 14,000 new individuals in the United States in 2001 and remains irreversibly fatal despite all available therapies. The current review focuses on the studies of apoptotic and survival signaling pathways in MM cells, which have both identified novel apoptotic and anti-apoptotic proteins and provided targets for novel therapeutics.

2
UI - 21241460
AU - Yamaguchi M; Ohno T; Miyata E; Toyoda H; Nishii K; Masuya M; Kita K; Shiku H
TI - Analysis of clonal relationship using single-cell polymerase chain reaction in a patient with concomitant mantle cell lymphoma and multiple myeloma.
SO - Int J Hematol 2001 Apr;73(3):383-5
AD - Second Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. waniwani@clin.medic.mie-u.ac.jp
We report a case of concomitant mantle cell lymphoma (MCL) and multiple myeloma (MM) in which we investigated the possibility of a clonal relationship. A 76-year-old man was diagnosed with MCL [immunoglobulin (Ig)M,D-kappa; stage IVB] and MM (IgG-kappa; stage I). Ig heavy chain (IgH) gene complementarity-determining region 3 in DNA from both the MCL tumor and from single MM cells from bone marrow smears was amplified to investigate whether there was a clonal relationship between MCL and MM. Sequence analysis revealed no clonal relationship between MCL and MM in our patient.

3
UI - 21274572
AU - Gonzalez-Rodriguez JL; Cevallos-Barrera E; Aviles Miranda A; Delgado-Gallardo S; Cortes-Arroyo H; Basantes-Pinos A; Perez M; Alvarado Cabrero I
TI - [Laryngeal plasmacytoma]
SO - Gac Med Mex 2001 Mar-Apr;137(2):153-6
AD - Departamento de Radioterapia, Hospital de Oncologia, Centro Medico Nacional, Instituto Mexicano del Seguro Social, Av Cuauhtemoc 330, Col. Doctores, Delegacion Cuauhtemoc, 06725, Mexico, D.F.
Solitary plasmocytoma is a rare presentation of plasma cell dyscrasia. About 1% od the patients can present with a extramedullary plasmocytoma; although bone presentation is the most frequent, in some cases, soft tissue can be affected. Radiotherapy remain as the election treatment. A case of primary plasmocytoma of the larynx is presented. The patient is alive after radiotherapy. Discussion about the clinical differentiation and also a review of the literature is present.

4
UI - 21301340
AU - Finney H; Williams AH; Price CP
TI - Serum cystatin C in patients with myeloma.
SO - Clin Chim Acta 2001 Jul 5;309(1):1-6
AD - Department of Clinical Biochemistry, The Royal London Hospital, Barts and The London NHS Trust, Whitechapel, E1 1BB, London, UK. Hazel.Finney@bartsandthelondon.nhs.uk
BACKGROUND: Cystatin C is a low molecular weight protein thought to be synthesised by all nucleated cells and freely filtered by the kidney. It has been proposed as a marker for GFR; however, it has been suggested that there may be limitations to its use, because it may be over-expressed in some tumour cells and the abnormal tissue growth may also lead to an increased circulating level. METHODS: We investigated the serum cystatin C levels in 60 patients with myeloma, comparing results with those for serum creatinine, beta(2)-microglobulin and the paraprotein concentration. Results: We found no correlation between cystatin C and the paraprotein concentration in these patients. CONCLUSION: These results suggest that disease burden does not correlate to the circulating level of cystatin C in patients with myeloma.

5
UI - 21375188
AU - Shinde A; Matsumae H; Maruyama A; Oida J; Kawamoto Y; Kouhara N; Oka N; Shirase T; Kitaichi M; Akiguchi I; Shibasaki H
TI - [A patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma]
SO - Rinsho Shinkeigaku 2001 Feb-Mar;41(2-3):121-5
AD - Department of Neurology, Kyoto University Graduate School of Medicine.
We here reported a 54-year-old female patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. She was found to have scattered tumor in 1990. Although the tumor had slowly grown for the last 10 years, she showed no clinical symptoms. Numbness and weakness of lower extremities began in June 1999, and she was referred to Kyoto University Hospital on Oct. 21 1999 for evaluation of progressive symptoms. She had skin pigmentation, edema of the lower extremities, lymphadenopathy, muscle weakness and sensory disturbance in a glove-and-stocking distribution. Serological examination showed monoclonal IgG-lambda gammopathy. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Microscopic studies on biopsied sural nerve demonstrated mild decrease of myelinated fibers. Immunohistochemically, the pulmonary tumor was defined as an IgG (lambda type) plasmacytoma. After treatment with melphalan-prednisolone therapy, the neurological symptoms improved along with decrease of serum VEGF levels as well as the size of pulmonary plasmacytoma. This is the first report of a patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. This case suggests that growth of pulmonary plasmacytoma might have played an important role in the overproduction of VEGF and thus development of Crow-Fukase syndrome.

6
UI - 21356199
AU - Xagoraris I; Paterakis G; Zolota B; Zikos P; Maniatis A; Mouzaki A
TI - Expression of granzyme B and perforin in multiple myeloma.
SO - Acta Haematol 2001;105(3):125-9
AD - Experimental Haematology and Transfusion Medicine, Medical School, University of Patras, Patras, Greece.
Multiple myeloma (MM) remains an incurable disease by conventional therapy. MM tumor cells evade the immune system and can induce immunosuppression by producing immunomodifying agents such as TGF-beta, FasL, vascular endothelial growth factor and Muc-1. In the present study, we show that bone marrow cells from a patient suffering from MM IgG/k type, stage IIIA, when cultured, expressed granzyme B and perforin, normally expressed exclusively by cytotoxic T cells (CTLs) and natural killer (NK) cells. In addition, phenotypic analysis revealed that the cultured cells were activated antigen-presenting cells with NK targeting capacity. We propose that expression of these cytolytic enzymes may constitute an additional adoptive mechanism by the tumor cells to actively destroy the host immune effector cells. Copyright 2001 S. Karger AG, Basel

7
UI - 21385720
AU - Hideshima T; Chauhan D; Schlossman R; Richardson P; Anderson KC
TI - The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.
SO - Oncogene 2001 Jul 27;20(33):4519-27
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA 02115, USA.
In this study we demonstrate that tumor necrosis factor alpha (TNFalpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNFalpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFalpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFalpha-induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFalpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.

8
UI - 21395234
AU - Hajek R; Koristek Z; Vinklarkova J; Janovska E; Klabusay M; Doubek M; Dvorakova D; Bourkova L; Dusek L; Adler J; Mayer J; Vorlicek J
TI - [Activation of autologous hematopoietic stem cell transplants with interleukin-2]
SO - Cas Lek Cesk 2001 Jul 19;140(14):430-5
AD - Interni hematoonkologicka klinika FN, Brno-Bohunice. r.hajek@fnbrno.cz
BACKGROUND: Recent findings of the role of the immunity in eradication of residual tumour tissue after autologous transplantation rejection leading to extensive studies on T-cell mediated specific antitumor effects or nonspecific NL-cell mediated anticancer effects. We have evaluated on the methods of adoptive cell therapy--IL-2 activation of autologous graft in the preclinical conditions. In laboratory conditions we have manipulated with autologous grafts form patients suffering with chronic myelocytic leukemia and patients suffering with multiple myeloma. METHODS AND RESULTS: Autologous graft was activated with IL-2 during 24-hours cultivation period in X-Vivo 10 medium with heparine, glutamine and Dnase. Quality of grafts after cultivation, contamination and activation of T and NK cell were evaluated. No significant differences between IL-2 activated graft and control were found. Results of autologous graft quality (CD34+, CFU-GM) were comparable with already published results. Quality of final product allowed starting of clinical experimental trials. CONCLUSIONS: We have proved the possibility to use IL-2 activated autologous graft in the clinical conditions. Based on our preclinical results experimental clinical trials have been initiated in patients suffering from chronic myelocytic leukemia and multiple myeloma.

9
UI - 21385073
AU - Mendes RV; Martins AR; de Nucci G; Murad F; Soares FA
TI - Expression of nitric oxide synthase isoforms and nitrotyrosine immunoreactivity by B-cell non-Hodgkin's lymphomas and multiple myeloma.
SO - Histopathology 2001 Aug;39(2):172-8
AD - Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil.
AIMS: Nitric oxide synthases (NOS) are isoenzymes that catalyse the synthesis of nitric oxide (NO). The three main NOS isoforms are: NOS1 or neuronal, NOS2 or inducible, and NOS3 or endothelial. NO plays both physiological and pathological roles, depending on its rate of synthesis and concentration, cellular source and microenvironment. Apoptosis is an important biological factor in low-grade lymphomas, and NO is able to prevent apoptosis. In-situ expression of NOS and synthesis of NO have been shown in several malignant tumours, but not in lymphoid neoplasms. This study evaluates whether human B-cell neoplasms express NOS isoforms, and nitrotyrosine (NY), which is usually interpreted as a marker of NO. METHODS AND RESULTS: We studied the expression of NOS-IR isoforms and NY-IR in 16 cases of B-cell non-Hodgkin's lymphoma (NHL) (five follicle centre cell lymphoma, four small lymphocytic/CLL, and seven diffuse large cell lymphoma), and 10 cases of multiple myeloma (MM). NOS1 was expressed in 5/10 cases of MM, and 15/16 cases of NHL. NOS2 was detected in all cases of MM, and in 14/16 cases of NHL, whereas NOS3 was positive in 3/10 of MM and in only in 1/16 cases of NHL. The expression of NY-IR was observed in 70% of MM cases, and in all cases of B-cell NHL, in a dot-like pattern in few tumour cells. CONCLUSIONS: B-cell neoplasms express neuronal and inducible NOS, and nitrotyrosine. Taken together, our results suggest that B-cell neoplasms can produce NO. The role of NO in the biology, diagnosis and prognosis of B-cell neoplasms remains to be established.

10
UI - 21396208
AU - Rajkumar SV; Kyle RA
TI - Thalidomide in the treatment of plasma cell malignancies.
SO - J Clin Oncol 2001 Aug 15;19(16):3593-5

11
UI - 21379829
AU - Sirohi B; Powles R; Kulkarni S; Rudin C; Saso R; Rigg A; Horton C; Singhal S; Mehta J; Treleaven J
TI - Glomerular filtration rate prior to high-dose melphalan 200 mg/m(2) as a surrogate marker of outcome in patients with myeloma.
SO - Br J Cancer 2001 Aug 3;85(3):325-32
AD - Leukaemia Unit, Royal Marsden NHS Trust, Surrey, UK.
We correlated age and body surface area corrected glomerular filtration rate (GFR) at the time of high-dose melphalan (HDM) administration with treatment-related toxicity (TT), time to disease progression and survival. Between 8/85 and 6/98, 144 newly diagnosed myeloma patients with a median age of 53 years (range, 31-72) received infusional chemotherapy with vincristine, doxorubicin and methylprednisolone, with/without cyclophosphamide or verapamil, followed by HDM 200 mg/m(2)and stem cell rescue. An additional patient received HDM at diagnosis. GFR was below normal in 38 patients (26%). At presentation, patients with low GFR at the time of HDM had higher serum creatinine, beta(2)M, stage III disease, calcium and Bence-Jones proteinuria. Toxic deaths post-HDM were similar in both groups (2/38 (5%) vs. 4/107 (4%)), though patients with low GFR had more oral mucositis (P< 0.0001), diarrhoea (P = 0.005) and infections (P = 0.04). The response and relapse rates of the 2 groups were not substantially different, but the median overall survival (OS) was significantly shorter in patients with low GFR (5.1 vs 7.5 years, P = 0.015). Multivariate analysis showed that a normal GFR and being in CR at the time of HDM were predictive of longer OS. We conclude that in context of high-dose chemotherapy for myeloma, dose of melphalan should not be modified in patients with low GFR and that early intensive treatment at relapse may improve results in patients with abnormal renal function. Copyright 2001 Cancer Research Campaign.

12
UI - 21215395
AU - Shuke N; Okizaki A; Yamamoto W; Usui K; Aburano T
TI - Accumulation of Tc-99m HMDP in extramedullary plasmacytoma of the stomach.
SO - Clin Nucl Med 2001 Apr;26(4):354-5
AD - Department of Radiology, Asahikawa Medical College, Japan.

13
UI - 21237430
AU - Goldman DA
TI - Thalidomide use: past history and current implications for practice.
SO - Oncol Nurs Forum 2001 Apr;28(3):471-7; quiz 478-9
AD - Cancer Institute of New Jersey, New Brunswick, USA.
PURPOSE/OBJECTIVES: To review the history of thalidomide, examine fears emanating from its renewed usage, and discuss the nurse's critical role in patient education. DATA SOURCES: Published articles, abstracts, books, and clinical experience. DATA SYNTHESIS: In the early 1960s, the teratogenic effects of thalidomide became widely known. The words thalidomide and birth defects became permanently linked as a result of pregnant women who used thalidomide as a sedative, thus giving birth to children with horrific birth defects. As researchers look at novel properties of drugs and new indications in the oncologic setting, thalidomide has made a comeback, particularly in the treatment of multiple myeloma. Patient education is important to combat fear in using and prescribing thalidomide and is essential in preventing birth defects and other side effects associated with thalidomide use. CONCLUSIONS: Nurses are vital in the patient-education process, yet on extensive nursing literature search revealed limited publications regarding thalidomide. Nurses can prevent thalidomide-associated birth defects through comprehensive patient education and can assist patients in decreasing any anxiety related to potential and actual side effects. IMPLICATIONS FOR NURSING PRACTICE: With careful patient monitoring and comprehensive education of physicians, nurses, and patients, it is possible to reap the benefits of thalidomide and avoid the tragedy of misues. Nurses are in the forefront of education, and their expertise will empower patients to use thalidomide responsibly.

14
UI - 21361153
AU - Porrata LF; Gertz MA; Inwards DJ; Litzow MR; Lacy MQ; Tefferi A; Gastineau DA; Dispenzieri A; Ansell SM; Micallef IN; Geyer SM; Markovic SN
TI - Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma.
SO - Blood 2001 Aug 1;98(3):579-85
AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Autologous stem cell transplantation (ASCT) improves survival in patients with previously untreated multiple myeloma (MM) and relapsed, chemotherapy-sensitive, aggressive non-Hodgkin lymphoma (NHL). Lower relapse rates seen in allogeneic stem cell transplantation have been related to early absolute lymphocyte count (ALC) recovery as a manifestation of early graft-verus-tumor effect. In ASCT, the relation between ALC recovery and clinical outcomes in MM and NHL was not previously described. This is a retrospective study of patients with MM and NHL who underwent ASCT at the Mayo Clinic between 1987 and 1999. The ALC threshold was determined at 500 cells/microL on day 15 after ASCT. The study identified 126 patients with MM and 104 patients with NHL. The median overall survival (OS) and progression-free survival (PFS) times for patients with MM were significantly longer in patients with an ALC of 500 cells/microL or more than patients with an ALC of fewer than 500 cells/microL (33 vs 12 months, P <.0001; 16 vs 8 months, P <.0003, respectively). For patients with NHL, the median OS and PFS times were significantly longer in patients with an ALC of 500 cells/microL or more versus those with fewer than 500 cells/microL (not reached vs 6 months, P <.0001; not reached vs 4 months, P <.0001, respectively). Multivariate analysis demonstrated day 15 ALC to be an independent prognostic indicator for OS and PFS rates for both groups of patients. In conclusion, ALC is correlated with clinical outcome and requires further study. (Blood. 2001;98:579-585)

15
UI - 21361178
AU - De Vos J; Couderc G; Tarte K; Jourdan M; Requirand G; Delteil MC; Rossi JF; Mechti N; Klein B
TI - Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.
SO - Blood 2001 Aug 1;98(3):771-80
AD - INSERM U475, Unit for Cellular Therapy, CHU Montpellier, 99 Rue Puech Villa, 34197 Montpellier Cedex 5, France.
In multiple myeloma (MM), the growth of primary plasma cells depends not only on interleukin-6 (IL-6), but also on additional unidentified signals delivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study identified genes that are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. These genes encode the oncogenic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) that is an epithelial autocrine tumor growth factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan-1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the Wnt pathway actor Frizzled-related protein (FRZB), and the Notch receptor ligand Jagged 2. These data, obtained with the Atlas cDNA array, were confirmed by reverse transcriptase-polymerase chain reaction or protein analysis or both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was documented in purified primary malignant plasma cells from patients with plasma cell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyclonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the potency and the biologic relevance of cDNA arrays used to analyze simultaneously a large panel of intercellular signaling genes and, by identifying several genes overexpressed in malignant plasma cells, opens new fields of investigation in MM biology. (Blood. 2001;98:771-780)

16
UI - 21361182
AU - Grad JM; Bahlis NJ; Reis I; Oshiro MM; Dalton WS; Boise LH
TI - Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells.
SO - Blood 2001 Aug 1;98(3):805-13
AD - Department of Microbiology and Immunology, Division of Hematology and Oncology, Sylvester Cancer Center, University of Miami School of Medicine, Miami, FL 33101, USA.
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by slow-growing plasma cells in the bone marrow (BM). Patients with MM typically respond to initial chemotherapies; however, essentially all progress to a chemoresistant state. Factors that contribute to the chemorefractory phenotype include modulation of free radical scavenging, increased expression of drug efflux pumps, and changes in gene expression that allow escape from apoptotic signaling. Recent data indicate that arsenic trioxide (As(2)O(3)) induces remission of refractory acute promyelocytic leukemia and apoptosis of cell lines overexpressing Bcl-2 family members; therefore, it was hypothesized that chemorefractory MM cells would be sensitive to As(2)O(3). As(2)O(3) induced apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and U266/Bcl-x(L). The addition of interleukin-6 had no effect on cell death. Glutathione (GSH) has been implicated as an inhibitor of As(2)O(3)-induced cell death either through conjugating As(2)O(3) or by sequestering reactive oxygen induced by As(2)O(3). Consistent with this possibility, increasing GSH levels with N-acetylcysteine attenuated As(2)O(3) cytotoxicity. Decreases in GSH have been associated with ascorbic acid (AA) metabolism. Clinically relevant doses of AA decreased GSH levels and potentiated As(2)O(3)-mediated cell death of all 4 MM cell lines. Similar results were obtained in freshly isolated human MM cells. In contrast, normal BM cells displayed little sensitivity to As(2)O(3) alone or in combination with AA. Together, these data suggest that As(2)O(3) and AA may be effective antineoplastic agents in refractory MM and that AA might be a useful adjuvant in GSH-sensitive therapies. (Blood. 2001;98:805-813)

17
UI - 21369579
AU - Chiriva-Internati M; Wang Z; Xue Y; Bumm K; Hahn AB; Lim SH
TI - Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk.
SO - Eur J Immunol 2001 Aug;31(8):2277-83
AD - Center for Immunology and Microbial Disease and Department of Medicine, Albany Medical College, Albany, NY 12208, USA.
We recently found that sperm protein 17 (Sp17), a spermatozoa-restricted protein, is aberrantly expressed on the tumor cells in patients with multiple myeloma (MM). It may therefore be possible to generate donor-derived Sp17-specific CTL for administration following allogeneic stem cell transplant to augment graft-versus-myeloma (GVM) effect without inducing a global GVHD. To assess this approach, we have produced recombinant Sp17 protein and used Sp17 protein-pulsed dendritic cells to generate HLA class I-restricted Sp17-specific CTL from a previously unimmunized healthy donor. These CTL were able to lyse autologous Epstein-Barr virus-transformed lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA-A1 and HLA-B27 restricted. Cytotoxicity could be blocked by antibodies against monomorphic HLA class I, HLA-A1 and HLA-B27 molecules but not HLA class II molecules. Most importantly, the CTL lysed HLA class I-matched Sp17-positive tumor cells, suggesting that Sp17 is processed and presented in association with the HLA class I molecules in Sp17-positive tumor cells in a concentration and configuration that could be recognized by recombinant protein-primed CTL. Analysis by flow cytometry of the CTL indicated that they were predominantly CD8 in phenotype and they produced IFN-gamma and very little IL-4. Our results suggest the potential for the generation and administration of donor-derived Sp17-specific CTL to augment GVM without inducing GVHD following allogeneic stem cell transplant for MM.

18
UI - 21420144
AU - Svaldi M; Tappa C; Gebert U; Bettini D; Fabris P; Franzelin F; Osele L; Mitterer M
TI - Technetium-99m-sestamibi scintigraphy: an alternative approach for diagnosis and follow-up of active myeloma lesions after high-dose chemotherapy and autologous stem cell transplantation.
SO - Ann Hematol 2001 Jul;80(7):393-7
AD - Department of Haematology and Bone Marrow Transplantation Center, Regional Hospital, Bozen/Bolzano, Italy.
Technetium-99m-sestamibi (MIBI) is a radionuclide tracer taken up by different malignant tumors. A total of 88 MIBI scans were carried out in 20 individuals with monoclonal gammopathy of unknown significance (MGUS) and 10 patients during follow-up for other cancers. Of these 58 MIBI scans were carried out in 46 myeloma patients: 15 at diagnosis, 14 during conventional chemotherapy, and 29 following high-dose sequential therapy and autologous peripheral blood progenitor support. A positive MIBI scan was exhibited by lof 10 with non-myeloma cancers and 2 of 20 with MGUS. In contrast, all stage II and III multiple myelomas (MM) were positive at diagnosis. Therefore, the sensitivity of the MIBI scan at diagnosis was 100%, whereas the specificity in this cohort was 93%. Four different MIBI patterns could be distinguished in MM patients: physiological, focal, diffuse, and extramedullary uptakes. In comparison to conventional skeletal radiographs, MIBI scans recognized a higher number of myeloma lesions at diagnosis. MIBI scans remained positive in all patients during conventional chemotherapy, and there was a direct correlation between MIBI result and clinical outcome of patients following high-dose therapy. Eighteen patients had a negative MIBI scan: 9 were in complete remission (CR), 8 in partial remission (PR), and 1 had progressive disease. Eleven patients showed lesions on the MIBI scan: 4 were in PR, 5 had progressive disease, 1 had a minimal response, and only 1 was in CR. A diffuse MIBI pattern reflected a higher bone marrow plasma cell number. In five patients, histologically or cytologically verified soft tissue myeloma lesions were correctly diagnosed by MIBI scan, while all plain radiographs showed none of them. MIBI has proven to be an effective tool in diagnosing biologically active myeloma.

19
UI - 21213524
AU - Badros A; Barlogie B; Morris C; Desikan R; Martin SR; Munshi N; Zangari M; Mehta J; Toor A; Cottler-Fox M; Fassas A; Anaissie E; Schichman S; Tricot G; Aniassie E
TI - High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions.
SO - Blood 2001 May 1;97(9):2574-9
AD - Myeloma and Transplantation Research Center and Department of Pathology, University of Arkansas for Medical Sciences and Veterans Health System, Little Rock, USA. badrosashrafz@exchange.uams.edu
Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/m(2) (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No TRM was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and DLI. Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure.

20
UI - 21213418
AU - Pace L; Catalano L; Del Vecchio S; Di Gennaro F; De Renzo A; Sica G; Califano C; Tedesco N; Borrelli G; Rotoli B; Salvatore M
TI - Predictive value of technetium-99m sestamibi in patients with multiple myeloma and potential role in the follow-up.
SO - Eur J Nucl Med 2001 Mar;28(3):304-12
AD - Cattedra di Medicina Nucleare, Dipartimento di Scienze Biomorfologiche e Funzionali, Facolta di Medicina e Chirurgia, Universita Federico II, via Pansini 5, 80131 Napoli, Italy. pace@unina.it
Technetium-99m 2-methoxyisobutylisonitrile (99mTc-MIBI or setamibi) has recently been proposed for use in the evaluation of multiple myeloma (MM). The aims of this study were to investigate its potential predictive value in patients with MM and its possible role in the follow-up. Thirty patients with MM who had undergone two 99mTc-MIBI scintigraphic studies at least 2 months apart constituted the study group; 22 of them received chemotherapy in the interval between the two scans. The scans were classified as showing pattern N when only physiological uptake was present, pattern D when diffuse bone marrow uptake was observed, pattern F when areas of focal uptake of the tracer were evident, and pattern F + D when both D and F patterns were observed. Comparative 99mTc-MIBI scintigraphy was considered indicative of disease progression when there was a worsening of the pattern (i.e. from N to D, or from N or D to F or to F + D) or an increase in the pattern D semiquantitative score. It was considered indicative of disease improvement when the opposite trend was observed; otherwise, it was considered to document a stable condition. A significant association was observed between the baseline scintigraphic pattern and clinical status at follow-up in the group of patients evaluated after chemotherapy (chi 2 = 16.7, P < 0.05). A negative baseline 99mTc-MIBI scintigram showed a high predictive accuracy (100%) for remission, while the presence of pattern F or F + D was often associated with a less favourable outcome. A multivariate analysis showed that 99mTc-MIBI uptake pattern has an added value in relation to known prognostic variables such as C-reactive protein. 99mTc-MIBI scintigraphy patterns at follow-up were significantly associated with the clinical status evaluated after chemotherapy (chi 2 = 32.6, P < 0.0001). Considering pattern N as indicating remission, pattern D stable condition, and pattern F or F + D progressive disease, a high concordance between scintigraphic findings and clinical status was found in the 22 patients undergoing chemotherapy (91%). Variation in 99mTc-MIBI findings comparing baseline and follow-up evaluations was significantly associated with clinical status both in patients undergoing chemotherapy (chi 2 = 26.5, P < 0.0005) and in those not undergoing chemotherapy (chi 2 = 8.0, P < 0.005). In conclusion, the results of this study suggest a prognostic value of 99mTc-MIBI scintigraphy in patients with MM and a potential role during the follow-up.

21
UI - 21303196
AU - Ng MH; To KW; Lo KW; Chan S; Tsang KS; Cheng SH; Ng HK
TI - Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma.
SO - Clin Cancer Res 2001 Jun;7(6):1724-9
AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China. margaretng@cuhk.edu.hk
Death-associated protein (DAP) kinase is a novel gene regulating apoptosis induced by IFN-gamma. In B-cell malignancies, loss of DAP kinase expression is commonly associated with promoter hypermethylation. These characteristics of DAP kinase may be of particular relevance in multiple myeloma (MM), a B-lineage malignancy in which prolonged survival capacity of the malignant plasma cells may be critical in the induction and maintenance of tumor cells. PURPOSE: The involvement and potential role of DAP kinase in MM pathogenesis was examined. EXPERIMENTAL DESIGN: In this investigation, methylation-specific PCR was conducted on primary MM and MM cell lines. Methylation status findings were correlated with clinical parameters. RESULTS: We first demonstrated frequent DAP kinase hypermethylation in 24 of 36 primary MMs (20 of 26 at diagnosis and 4 of 10 with relapse/residual MM after treatment), 1 of 2 patients with monoclonal gammopathy of undetermined significance, and 1 of 3 MM cell lines studied. The high frequency of DAP kinase hypermethylation was similarly observed in MM of different stages, immunoglobulin isotypes, and histological grades, with or without plasmacytomas. Although not statistically significant, the overall survival of patients with DAP kinase methylation was notably shortened among 23 MM patients followed prospectively (P = 0.38 by Kaplan-Meier method and log-rank test). This preliminary finding suggests prognostic implications of DAP kinase in MM that may deserve further investigation. CONCLUSIONS: Our data suggest an important role for DAP kinase in MM tumorigenesis.

22
UI - 21315522
AU - Shimizu K; Imaida K
TI - Metastatic transitional cell carcinoma or nonsecretory multiple myeloma?
SO - Clin Lab Haematol 2001 Feb;23(1):67

23
UI - 21383996
AU - Chindia ML; Riyat MS; Nyong'o A
TI - Multiple myeloma presenting as a painful mandibular swelling: a case report.
SO - Dent Update 2001 Jun;28(5):258-60
AD - Faculty of Dental Sciences, University of Nairobi, Kenya.
Multiple myeloma is a disease characterized by monoclonal proliferation of plasma cells, the most differentiated stage of B-cells. Primary manifestation of multiple myeloma in the jawbones is rare. In the case reported here, a 29-year-old woman who presented with a right mandibular swelling after extraction of a mobile painful tooth turned out to have multiple myeloma. Current diagnostic criteria and management strategies of the disease are discussed.

24
UI - 21334513
AU - Besses C
TI - [40 years ago in Medicina Clinica. The introduction of melphalan in Spain]
SO - Med Clin (Barc) 2001 Jun 9;117(1):24-6
AD - Servei d'Hematologia Clinica. Grup de Recerca Hematologica. Hospital del Mar. IMAS. IMIM. Barcelona. cbessos@imas.imim.es

25
UI - 21358781
AU - Martin Reyes G; Garcia Gonzalez I; Alferez MJ; Martinez Gonzalez JM; Frutos MA
TI - [Intracytoplasmic crystals and Fanconi syndrome in a patient with IgA kappa myeloma]
SO - Nefrologia 2001 Mar-Apr;21(2):213-6
AD - Servicio de Nefrologia, Hospital Regional Universitario Carlos Haya, Avda. Carlos Haya, 82, 29010 Malaga.
A 45 year old man with IgA-Kappa myeloma had adult Fanconi Syndrome. Examination of renal biopsy revealed lesions in proximal tubules without glomerular lesions and without intratubular casts. By electron microscopy cytoplasmic crystalline inclusions were observed in renal proximal tubular epithelium. Increased plasma cells (28%) in bone marrow aspiration also contained crystalline inclusions. The treatment of myeloma produced partial remission of proliferative disease and Fanconi syndrome. We discuss the pathogenesis of Fanconi syndrome induced by light chains as well as the composition of crystalline deposits and the effects of treatment on Fanconi Syndrome.

26
UI - 21378186
AU - Thabard W; Collette M; Bataille R; Amiot M
TI - Protein kinase C delta and eta isoenzymes control the shedding of the interleukin 6 receptor alpha in myeloma cells.
SO - Biochem J 2001 Aug 15;358(Pt 1):193-200
AD - U463 Institut de Biologie, 9 quai Moncousu, 44093 Nantes cedex 01, France.
The soluble interleukin 6 receptor alpha is an agonistic molecule of interleukin 6 (IL-6) and is important in the biology of multiple myeloma. More precisely, it potentiates the deleterious effects of IL-6 during tumour progression, facilitating angiogenesis and bone resorption. Because the mechanisms involved in the shedding of the interleukin 6 receptor alpha (IL-6Ralpha) in multiple myeloma are not known, we have investigated them in the XG-6 human myeloma cell line. Here we provide evidence that PMA-induced IL-6Ralpha shedding is controlled by a metalloproteinase and by protein kinase C (PKC) isoenzymes that do not require Ca(2+) for their activation. We show that XG-6 cells express PKC-delta, -eta and -zeta isoenzymes. However, after stimulation with PMA, only PKC-delta and PKC-eta are activated, as shown by their translocation to the membrane. Treatment with PMA induces an increase in PKC-delta phosphorylation in its active loop. In addition, by using rottlerin, a specific inhibitor of PKC-delta, we demonstrate that PKC-delta is involved in the PMA-induced shedding of IL-6Ralpha. With the use of UO126, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway, we show that the PMA-induced IL-6Ralpha shedding is mediated in part by the MAPK pathway. Finally, whereas GF109203X, a general PKC inhibitor, inhibits the activation of ERK1/2 (extracellular signal-regulated protein kinase 1/2), rottlerin has no inhibitory effect, indicating that the Ras/MAPK activation is PKC-dependent but PKC-delta-independent. Taken together, these results suggest that the PMA-induced shedding of IL-6Ralpha is mediated by a PKC isoenzyme network.

27
UI - 21400201
AU - Fonesca R; Oken MM; Greipp PR; Eastern Cooperative Oncology Group Myeloma Group
TI - The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance.
SO - Blood 2001 Aug 15;98(4):1271-2

28
UI - 21384747
AU - Alyea E; Weller E; Schlossman R; Canning C; Webb I; Doss D; Mauch P; Marcus K; Fisher D; Freeman A; Parikh B; Gribben J; Soiffer R; Ritz J; Anderson K
TI - T-cell--depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect.
SO - Blood 2001 Aug 15;98(4):934-9
AD - Center for Hematologic Oncology and Department of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. edwin_alyea@dfci.harvard.edu
Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell--depleted allogeneic BMT was combined with prophylactic CD4(+) DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (> or = II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P =.13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell--depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (Blood. 2001;98:934-939)

29
UI - 21387281
AU - Liu Q; El-Deiry WS; Gazitt Y
TI - Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosis in myeloma cell lines.
SO - Exp Hematol 2001 Aug;29(8):962-70
AD - University of Texas Health Science Center, San Antonio, Tex., USA.
OBJECTIVE: We have previously shown that Adenovirus-p53 (Ad-p53) is a potent inducer of apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2 and that Apo2L/TRAIL is a potent inducer of apoptosis, independent of bcl-2. A study was designed to test the synergy between Ad-p53 and Apo2L/TRAIL in the induction of apoptosis in relation to the expression of DR4/DR5 and DcR1, in cells undergoing Ad-p53-induced apoptosis. METHODS: Replication deficient Ad-p53 and human recombinant Apo2L/TRAIL were used. Myeloma cells with mutated/w.t. p53 and varying expression of bcl-2 were used to test the effect of Ad-p53, Apo2L/TRAIL, or both, on apoptosis, measured by annexin V. RESULTS: Treatment with Ad-p53 resulted in a dose-dependent apoptosis concomitant with a dose-dependent increase in the expression of DR4/DR5 and a decrease in the expression of DcR1, in Ad-p53-sensitive cell lines. In these cells, addition of Apo2L/TRAIL to cells treated with Ad-p53 resulted in a dose-dependent increase in apoptosis. Myeloma cells resistant to Ad-p53 had high levels of DR4/DR5 and high levels of DcR1 and treatment with Ad-p53 did not reduce the expression of DcR1. Also, addition of Apo2L/TRAIL to Ad-p53 did not affect the level of apoptosis beyond the level of apoptosis observed with Apo2L/TRAIL alone. CONCLUSIONS: 1) Cotreatment with Ad-p53 and Apo2L/TRAIL resulted in additive apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2. 2) Resistance to Ad-p53 or to the combination of Ad-p53 and Apo2L/TRAIL was not due to the lack of adenovirus receptor (CAR) or low expression of DR4/DR5 but rather due to the relatively high expression of DcR1 receptor.

30
UI - 21387284
AU - Vacca A; Ria R; Presta M; Ribatti D; Iurlaro M; Merchionne F; Tanghetti E; Dammacco F
TI - alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells.
SO - Exp Hematol 2001 Aug;29(8):993-1003
AD - Department of Biomedical Sciences, University of Bari Medical School, Bari, Italy. avacca@hotmail.com
OBJECTIVE: The mechanisms used by human lymphoproliferative diseases to invade locally and metastasize are thought to be similar to those developed by solid tumors, including cell proliferation and secretion of extracellular matrix-degrading enzymes following adhesion to extracellular matrix proteins. Hence, the ability of Namalwa (Burkitt's lymphoma), U266 (multiple myeloma), and CEM (T-cell lymphoblastic leukemia) cells to interact with the extracellular matrix components vitronectin and fibronectin was determined. Fresh bone marrow plasma cells from patients with multiple myeloma also were studied. MATERIALS AND METHODS: Engagement of alpha(v)beta(3) integrin, formation and protein composition of focal adhesion contacts on the cell surface, phosphorylation of several signal transduction proteins in the contacts, cell proliferation, and enzyme secretion were studied following adhesion to vitronectin and fibronectin. RESULTS: All three lines adhered to immobilized vitronectin and fibronectin. Adhesion was fully prevented by neutralizing monoclonal anti-alpha(v)beta(3) integrin antibody. Integrin engagement caused the formation of phosphorylated pp60(src)/focal adhesion kinase complexes and the aggregation of focal adhesion plaques containing the beta(3) integrin subunit, the cytoskeletal proteins vinculin, cortactin, and paxillin, the tyrosine kinases focal adhesion kinase and pp60(src), the adapter protein Grb-2, and the mitogen-activated protein kinase ERK-2. Free and immobilized vitronectin and fibronectin stimulated the proliferation of cells under serum-free conditions and the production and release of urokinase-type plasminogen activator, and increased the release of the activated forms of matrix metalloproteinase-2 and matrix metalloproteinase-9 in an alpha(v)beta(3) integrin-dependent manner. Similar results were obtained in myeloma plasma cells. CONCLUSIONS: The demonstrated ability of lymphoid tumor cells to interact with the extracellular matrix components vitronectin and fibronectin via alpha(v)beta(3) integrin can be interpreted as evidence of a novel mechanism for their invasion and spreading. This interaction allows them to adhere to the substratum and enhances their proliferation and protease secretion.

31
UI - 21402971
AU - Wang LH; Yang XY; Mihalic K; Xiao W; Li D; Farrar WL
TI - Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3.
SO - J Biol Chem 2001 Aug 24;276(34):31839-44
AD - Intramural Research Support Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland 21702, USA.
Estrogen receptors (ERs)(1) highly expressed by multiple myeloma (MM) cells and stimulation of estrogenic ligands leads to cell apoptosis. Interleukin (IL)-6 is a major growth factor in the pathogenesis of MM. However, little is known concerning the molecular consequences of ER activation on IL-6-regulated MM cell growth. Here we show that the ER agonist 17 beta-estradiol completely abolished IL-6-inducible MM cell proliferation. By contrast, the ER antagonist ICI 182,780 overcame the inhibitory effect of estrogen. Estrogen blocked STAT3 DNA binding and transactivation but failed to affect the mRNA expression of IL-6 receptor chains or activation of JAK2 and STAT3. Estrogen-activated ER did not associate directly with STAT3. Estrogen induced the mRNA expression of PIAS3 (protein inhibitor of activated STAT3) and increased PIAS3 physical association with STAT3, suggesting a possible mechanism of STAT3 inhibition requiring PIAS3 as a co-regulator modulating the cross-talk between ER and STAT3. These data directly demonstrate STAT3 to be a molecular participant in ER inhibition of the IL-6 signaling pathway in human MM cells and provides the molecular basis for the potential use of estrogenic ligands in the treatment of MM or other tumors where IL-6 has an autocrine or paracrine role.

32
UI - 21409938
AU - Moehler TM; Hawighorst H; Neben K; Egerer G; Hillengass J; Max R; Benner A; Ho AD; van Kaick G; Goldschmidt H
TI - Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging.
SO - Int J Cancer 2001 Sep15;93(6):862-8
AD - Department of Hematology/Oncology/Rheumatology, University of Heidelberg, Heidelberg, Germany. Thomas_Moehler@med.uni-heidelberg.de
The aim of our study was to investigate the quantitative microcirculation parameters amplitude A (hypothetical intravascular volume) and exchange rate constant k(21) (hypothetical vascular permeability) by contrast-enhanced dynamic magnetic resonance imaging (dMRI) as markers of angiogenesis in multiple myeloma (MM). Therefore lumbar spine and spina iliaca superior posterior of 16 normal controls and 41 patients with active MM were assessed using a dMRI protocol with a pump controlled bolus infusion of Gadolinium-DTPA. Pharmacokinetic parameters, amplitude A and exchange rate constant k(21) were calculated according to a 2-compartment model. Color-coded parameter images were generated from pharmacokinetic data analysis and superimposed onto the conventional MR images. Amplitude A and k(21) parameters were significantly increased in patients with MM compared with controls (p = 0.001; media